The disposition in human patients of 3-methoxy-4-hydroxy phenylglycol (MHPG), a major metabolite of norepinephrine, has been modeled. The cerebrospinal fluid concentration of MHPG and the urinary excretion rates of its metabolites before and during treatment with desipramine (DMI) and zimelidine (ZIM) were used to evaluate the effect of drug treatment upon the central nervous system rate of production of MHPG. The central rate of production of MHPG was decreased (P less than .05) by 45.7 plus/minus 17.4% by DMI treatment and by 21.4 plus/minus 17.9% by ZIM treatment. A well-stirred model of liver metabolism has been applied to published data on the disposition of melatonin in humans. Melatonin can be described as a substance subject to a large first pass effect of hepatic metabolism. This first pass effect does not appear to account for all of the poor oral bioavailability of melatonin. Although it has been reported that the elimination rate of melatonin is decreased in patients with hepatic cirrhosis, the application of clearance concepts to the same data provides evidence that the endogenous production rate of melatonin is also decreased.